The long-term goals of our laboratory are to elucidate the molecular pathways involved in the behavioral and neuroendocrine responses to stress, and to determine how these mechanisms affect cognitive changes during development and aging. Importantly, chronic stress often results in alterations in behavior and physiology that are maladaptive, exacerbating both medical and psychiatric diseases. The calcium-stimulated adenylyl cyclases (ACs) provide a critical control point for the regulation of neuronal physiology, and have been implicated in activity-dependent alterations in neural function. To define the molecular pathways involved in the response to stress, we generated mice deficient (KO) in calcium-stimulated adenylyl cyclase type VIII (AC8). AC8 KO mice demonstrate compromise in calcium-stimulated AC activity in the hippocampus, impaired hippocampal CA1 long-term depression (LTD), and failure to activate CREB in the CA1 region after stress. Consistent with these biochemical and electrophysiological alterations in hippocampal function, AC8 KO mice do not demonstrate stress- induced learning. In this proposal, we seek to define the role of AC8 in transduction of stress-induced signals important for hippocampal LTD and alterations in behavior. Integrating molecular genetic, electrophysiological, and behavioral approaches, we will 1) develop an in vivo transgenic system that allows regulated expression of AC8 within the CA1 region of the hippocampus; 2) determine when during brain development and exposure to stress AC8 activation is required to impart stress- induced learning; 3) determine whether the alterations in neuronal function and behavior arise from resistance of CA1 neurons deficient in AC8 to the effects of glucocorticoids. The findings in these studies will serve as the basis for proposing modulation of AC8 action as a novel therapeutic approach to human psychiatric and chronic stress-generated disorders.